title: GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier.
abstract: The high metabolic requirements of the mammalian central nervous system require specialized structures for the facilitated transport of nutrients across the blood-brain barrier. Stereospecific high-capacity carriers, including those that recognize glucose, are key components of this barrier, which also protects the brain against noxious substances. Facilitated glucose transport in vertebrates is catalyzed by a family of carriers consisting of at least five functional isoforms with distinct tissue distributions, subcellular localizations and transport kinetics. Several of these transporters are expressed in the mammalian brain. GLUT-1, whose sequence was originally deduced from cDNAs cloned from human hepatoma and rat brain, is present at high levels in primate erythrocytes and brain endothelial cells. GLUT1 has been cloned and positionally mapped to the short arm of chromosome 1 (1p35-p31.3; refs 6-8). Despite substantial metabolic requirements of the central nervous system, no genetic disease caused by dysfunctional blood-brain barrier transport has been identified. Several years ago, we described two patients with infantile seizures, delayed development and acquired microcephaly who have normal circulating blood glucose, low-to-normal cerebrospinal fluid (CSF) lactate, but persistent hypoglycorrachia (low CSF glucose) and diminished transport of hexose into isolated red blood cells (RBC). These symptoms suggested the existence of a defect in glucose transport across the blood brain barrier. We now report two distinct classes of mutations as the molecular basis for the functional defect of glucose transport: hemizygosity of GLUT1 and nonsense mutations resulting in truncation of the GLUT-1 protein.
authors.affiliation: Howard Hughes Medical Institute and the Cox Institute, Philadelphia, Pennsylvania, USA.
authors.forename: G
authors.initials: G
authors.lastname: Seidner
authors.forename: M G
authors.initials: MG
authors.lastname: Alvarez
authors.forename: J I
authors.initials: JI
authors.lastname: Yeh
authors.forename: K R
authors.initials: KR
authors.lastname: O'Driscoll
authors.forename: J
authors.initials: J
authors.lastname: Klepper
authors.forename: T S
authors.initials: TS
authors.lastname: Stump
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: N B
authors.initials: NB
authors.lastname: Spinner
authors.forename: M J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: D C
authors.initials: DC
authors.lastname: De Vivo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D051272:Glucose Transporter Type 1; D006239:Haplotypes; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009004:Monosaccharide Transport Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D051381:Rats; D012640:Seizures / Q000235:genetics; D012867:Skin / Q000473:pathology; D013577:Syndrome
chemical_list: D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human; C495679:Slc2a1 protein, rat